| Summary: | FGF21 is a promising candidate for treating obesity, diabetes, and NAFLD; however, some of its pharmacological effects are sex-specific in mice with the <i>A<sup>y</sup></i> mutation that evokes melanocortin receptor 4 blockade, obesity, and hepatosteatosis. This suggests that the ability of FGF21 to correct melanocortin obesity may depend on sex. This study compares FGF21 action on food intake, locomotor activity, gene expression, metabolic characteristics, and liver state in obese <i>A<sup>y</sup></i> males and females. <i>A<sup>y</sup></i> mice were administered FGF21 for seven days, and metabolic parameters and gene expression in different tissues were assessed. Placebo-treated females were more obese than males and had lower levels of blood insulin and liver triglycerides, and higher expression of genes for insulin signaling in the liver, white adipose tissue (WAT) and muscles, and pro-inflammatory cytokines in the liver. FGF21 administration did not affect body weight, and increased food intake, locomotor activity, expression of <i>Fgf21</i> and <i>Ucp1</i> in brown fat and genes related to lipolysis and insulin action in WAT regardless of sex; however, it decreased hyperinsulinemia and hepatic lipid accumulation and increased muscle expression of <i>Cpt1</i> and <i>Irs1</i> only in males. Thus, FGF21’s beneficial effects on metabolic disorders associated with melanocortin obesity are more pronounced in males.
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